An aqueous eye drop comprising DFNa which is a non-steroidal anti-inflammatory agent has been used for protecting a patient from suffering from post-operative inflammatory conditions and complications during and after operations, when the patient is subjected to cataract surgery, because of the strong prostaglandin biosynthesis-inhibitory action of the anti-inflammatory agent. If the non-steroidal anti-inflammatory agents are used in eye drops, most of these anti-inflammatory agents have an irritating action to mucous membranes and eyes and an effect of causing a strong ocular pain.
The inventors of this invention have provided an anti-inflammatory eye drop which comprises at least one non-steroidal anti-inflammatory agents selected from the group consisting of ibuprofen, indometacin, ketoprofen, naproxen and flufenamic acid as a basis and a salt of calcium or magnesium with a physiologically acceptable acid as an ocular irritation-alleviating agent Japanese Examined Patent Publication (hereinafter referred to as "J.P. KOKOKU) No. Hei 1-19362! in order to alleviate the ocular irritation and the ocular pain induced by the non-steroidal anti-inflammatory agent. In addition, the inventors have provided an anti-inflammatory eye drop which comprises DFNa and polyoxyethylene sorbitan monooleate or .alpha.- and .beta.-cyclodextrin, as an auxiliary agent for dissolution, in an amount ranging from 5 to 10 times (weight basis) the amount of DFNa (J.P. KOKOKU No. Hei 2-6329). Moreover, the inventors of this invention have developed an eye drop which comprises a chemically modified .beta.-cyclodextrin in combination with DFNa and which does not cause ocular irritation immediately after being dropped in the eyes and is excellent in storage stability and filed a patent application Japanese Un-Examined Patent Publication (hereinafter referred to as "J.P. KOKAI") No. Hei 6-16547!.
Furthermore, there has been proposed a therapeutic agent comprising an aqueous solution which contains DFNa as an effective component, a buffering agent, an auxiliary agent for dissolution and a preservative and which further comprises 2-amino-2-hydroxymethyl-1,3-propanediol or a homologue thereof having up to 10 carbon atoms as a stabilizer for the effective component and the preservative (J.P. XOKAI No. Sho 62-242617). On the other hand, there have been proposed, as cyclodextrin-containing eye drops, an anti-inflammatory ophthalmic solution which comprises 2-(2-fluoro-4-biphenylyl)propionic acid or a salt thereof and .beta.-cyclodextrin (hereinafter referred to as ".beta.-CyD") or .gamma.-CyD (J.P. KOKOKU No. Hei 3-30571); an anti-inflammatory ophthalmic solution which comprises 2-(2-fluoro-4-biphenylyl)propionic acid or a salt thereof, .beta.-CyD or .gamma.-CyD and a calcium salt or a magnesium salt (J.P. KOKAI No. Sho 60-136516); or an aqueous ophthalmic solution which comprises 3,4-dihydro-2,8-diisopropyl-3-thioxo-2H-1,4-benzoxadine-4-acetic acid or a salt thereof as a basis and cyclodextrin (J.P. KOKAI No. Hei 5-213757).
The calcium or magnesium salt of a physiologically acceptable acid shows a satisfactory effect of alleviating the ocular irritation of the resulting eye drop, but the eye drop containing the same suffers from a problem such that it is insufficient in the long term storage stability. The .alpha.-cyclodextrin as disclosed in J.P. KOKOKU No. Hei 2-6329 does not have any effect of alleviating the ocular irritation due to DFNa, while .beta.-CyD shows a weak ocular irritation-alleviating effect, but the effect is insufficient. Thereafter the inventors of this invention have found out that the incorporation of a chemically modified water-soluble .beta.-CyD into such an eye drop containing DFNa in an amount of 7 to 50 times the amount of the latter results in the formation of an eye drop having excellent ocular irritation-alleviating effect and excellent storage stability (J.P. KOKAI No. Hei 6-16547). However, the incorporation thereof does not ensure a sufficient ocular irritation-alleviating effect at a DFNa concentration of higher than 0.1%. The eye drop exemplified in J.P. KOKAI No. Sho 62-242617 shows considerably high storage stability, but strongly irritates the eyes immediately after it is dropped in the eyes and therefore, these conventional eye drops have not yet been satisfied.
Moreover, J.P. KOKAI Nos. Sho 60-136516 and Hei 5-213757 which are improved inventions of that disclosed in the foregoing J.P. KOKOKU No Hei 3-30571 disclose that .beta.-CyD and .gamma.-CyD have an effect of alleviating the ocular irritation caused by the effective component, but .gamma.-CyD does not show a sufficient effect in the both cases.
On the other hand, .gamma.-CyD has been known to show local safety identical to or higher than that observed for the chemically modified water-soluble .beta.-CyD (Uekama, Pharm. Tech. Japan, 1991, 7(2), p. 143). It has conventionally been difficult to mass-produce .gamma.-CyD and the price thereof is very high, i.e., about 100 times that of .beta.-CyD. Therefore, .gamma.-CyD has not been used at all from the economical standpoint. However, there has recently been developed a new technique for manufacturing the same, it has been put on the market at a low price and has attracted special interest recently as an additive for drugs.